Process for preparing substituted uracils



United States Patent 3,254,082 PROCESS FOR PREPARING SUBSTITUTED URACILS Harvey M. Loux, Hockessin, Del., and Edward J. Soboczenski, Chadds Ford, Pa., assignors to E. I. do Pout de Nemours and Company, Wilmington, Del., 21 corporation of Delaware No Drawing. Filed June 3, 1963, Ser. No. 284,835 9 Claims. (Cl. 260260) This application is a continuation-in-part of abandoned application Serial No. 12,957, filed March 7, 1960, and copending application Serial No. 123,636, filed July 13, 1961, now abandoned.

This invention relates to processes for the preparation of substituted uracils and their salts.

The compounds made according to this invention are of the formula R is alkyl of 1 through 10 carbon atoms, substituted alkyl of 1 through 8 carbon atoms, aryl of through carbon atoms, substituted phenyl, aralkyl of 5 through 13 carbon atoms, substituted aralkyl of 5 through 13 carbon atoms, alkenyl of 3 through 8 carbon atoms, alkynyl of 3 through 8 carbon atoms, cycloalkyl of 3 through 12 carbon atoms, cycloalkenyl of 4 through 12 carbon atoms, cycloalkyl alkyl of 4 through 13 carbon atoms, cycloalkenyl alkyl of 5 through 13 carbon atoms, (substituted cycloalkyDalkyl of 5 through 14 carbon atoms, or (substituted cycloalke nyl) alkyl of 5 through 14 carbon atoms;

R is hydrogen, chlorine, fluorine, bromine, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, alkenyl of 3 through 6 carbon atoms, cyano, alkylthio of 1 through 4 carbon atoms or Z-hydroxy alkyl of 2 through 6 carbon atoms;

R is alkyl of 1 through 5 carbon atoms;

X is oxygen or sulfur; and

M is hydrogen, sodium, potassium, or lithium.

In the above formula, R and R can be taken together by way of a methylene bridge to form a ring. This methylene bridge can be represented by the formula -(CH where n is 3, 4 or 5.

When M is sodium, potassium, or lithium, the negative charge of the molecule in Formula 1 is distributed throughout the ring because of electron shifts. For convenience, however, it is represented as in Formula 1.

In Formula 1, the term substituted alkyl is intended to include such radicals as Bromoalkyl of 1 through 10 carbon atoms, Chloroalkyl of 1 through 10 carbon atoms, Hydroxyalkyl of 1 through 8 carbon atoms, Alkoxyalkyl of 2 through 8 carbon atoms, Alkoxy carbonyl alkyl of 3 through 8 carbon atoms, and Cyanoalkyl of 2 through 8 carbon atoms.

Similarly, the term substituted phenyl embraces radicals such as Phenyl, Furfuryl, Naphthyl, o-Biphenyl, Pyridyl, Chlorophenyl,

Brom ophenyl,

Alkoxyphenyl,

Dibromophenyl,

Fluorophenyl,

Trichlorophenyl,

Alkylphenylof 7 through 11 carbon atoms, Dialkylphenyl of 8 through 12 carbon atoms, Chloroalkylphenyl of- 7 through 10 carbon atoms, Nitrochlorophenyl,

Nitrophenyl,

Dichloronitrophenyl,

Chloroalkoxyphenyl of 7 through 11 carbon atoms, Trifluoromethylphenyl,

Tetrahydronaphthyl, and

Indenyl.

The term substituted aralkyl. is intended to include such radicals as Furfuryl, Benzyl, Phenylalkyl of 8 through 11 carbon atoms (total),

. Chlorobenzyl,

Dichlorobenzyl,

- Alkylbenzyl of 8 through 11 carbon atoms (total),

Dialkylbenzyl of 9 through 13 carbon atoms (total), Nitrobenzyl, Alkoxybenzyl of 8 through 11 carbon atoms (total), and

- Naphthylmethyl.

The terms cycloalkyl, cycloalkenyl, cycloalkyl alkyl, and cycloalkenyl alkyl will include Cyclohexyl,

Cyclohexenyl,

Cyclohexylalkyl,

Cyclohexenylalkyl,

Cyclopentyl,

Cyclopentenyl,

Cyclopentylalkyl, Cyclopentenylalkyl,

Norbornyl,

Norbornenyl,

Norbornylalkyl,

Norbornenylalkyl,

Bicyclo (2,2,2) octyl,

Bicyclo (2,2,2) octenyl,

Bicyclo (2,2,2) octylalkyl,

Bicyclo (2,2,2) octenylalkyl, Cyclopropyl,

Cyclobutyl,

Cyclobutylalkyl,

Cyclobutenyl,

Cyclobutenylalkyl, Hexahydroindanyl, Tetrahydroindanyl, Hexahydroindenyl, Hexahydroindenyl alkyl, Tetrahydroindanyl alkyl, Hexahydroindanyl alkyl, Hexahydro-4,7-methanoindenyl, Tetrahydro-4,7-methanoindanyl, Hexahydro-4,7-methanoindanyl, Hexahydro-4,7-methanoindenyl alkyl, Tetrahydro-4,7-methanoindany1 alkyl, HeXahydro-4,7-methanoindanyl alkyl, Decahydronaphthyl, Decahydronaphthyl alkyl, Tetrahydronaphthyl, Tetrahydronaphthyl alkyl, Decahydro-l,4-methanonaphthyl, Decahydro-1,4-methanonaphthyl alkyl, Octahydro-1,4-methanonaphthyl,

3 Octahydro-1,4-methanonaphthyl alkyl, Decahydro-l,4-5,8-dimethanonaphthyl, Decahydro-1,4-5,8-dimethanonaphthyl alkyl, Octahydro-1,4-5,8-dimethanonaphthyl, and Octahydro-l,4-5,8-dimethanonaphthyl alkyl.

These cyclic substituents can be further substituted with alkyl groups of 1 through 4 carbon atoms, methoxy, chlorine or bromine.

The compounds produced according to the processes of this invention are herbicidally active and can be formulated with suitable inert carriers to give compositions which can be used to control undesired vegetation.

Those compounds produced according to these processes which are not substituted in the 5-position are. also useful as intermediates, which can react with typical electrophilic reagents such as halogens, nitric acid, formaldehyde, and thiocyanogen to form other herbicidal 3,5,6- trisubstituted uracils. Details regarding these phenomena can be found in copending application Serial No. 217,- 521, filed August 28, 1962.

All the steps involved in practicing the processes of this invention can be carried out in one reaction vessel. Intermediate compounds need not be isolated and purified.

The processes of this invention give substantially higher yields of the compounds of Formula 1 than was previously possible. These higher yields are obtained without the production of undesirable lay-products.

-It should be noted that the compounds produced according to the processes of this invention can be used directly as herbicides Without recrystallization.

The compounds of Formula 1 are prepared by a sequence of three reactions. The first reaction comprises heating a mono-substituted urea or thiourea with a fl-keto ester in the presence of a catalyst to form a 3-(3-sub'stituted ureido)-2,3unsaturated ester. The second reaction comprises heating this unsaturated ester with a strong base. This efiects ring closure and produces the corresponding 3,6-substituted uracil salt. If desired, this salt 40 can then :be converted to the 3,6-substituted uracil by reacting it with an acid.

This three-step reaction sequence is illustrated by the following equations:

where R is hydrogen or an alkyl group of 1 to 4 carbon atoms,

and 7 5 If this replacement is made, the process proceeds according to the following squence:

PROCEDURE AND PROCESS VARIABLES FOR STEP 1 A mixture of B-keto ester or 'y-l-actone, catalyst, and mono-substituted urea or thiourea stirred and distilled to remove evolved water. For maximum yields, the reaction temperature should be kept low and water should be removed as rapidly as possible.

In order to obtain maximum theoretical conversion, the mole ratio of the fi-keto ester or 'y-lactone to the mono-substituted urea or thiourea should be about 1 to 1. In practice, the ester-lactone/ureav mole ratio can vary from 0.7 to 1.30 moles of ester or lactone for each mole of urea.

Although the reaction proceeds satisfactorily in the absence of a liquid medium, it is facilitated if it is carried out in such a medium. This liquid must be a substance which does not react with the reagents or products involved in the entire process under the described reaction conditions, and preferably boils in the temperature range of 50 C. to C. at pressures of 25-1500 mm. of mercury. Inert liquids which can :be used for this reaction include cyclohexane, hexane, heptane, octane, o-dichlorobenzene, benzene, toluene, xylene, chlorobenzene, diisobutylene, or mixtures of these liquids with a water-miscible liquid such as dioxane. Xylene is preferred. Preferably about 0.3 to 3 parts by weight of the inert liquid are used for each part of reactants.

When the reaction is carried on without an inert liquid medium, the reaction temperatures are maintained in the range of 50 to 110 C. until approximately the theoretical amount of water is collected by distillation. The pressure should be such that the reaction mixture boils in the proper temperature range.

6 Ring closure occurs rapidly at this temperature and the corresponding salt of the desired 3,6-substituted uracil is obtained as a residue by removing the liquid medium. These salts can be used directly as aqueous solutions in It is preferred to carry on the reaction in an inert liquid 5 herbicidal applications. water-immiscible medium because the water formed dur- A technical grade of the uracil salt can be obtained in ing the reaction can be more rapidly removed by azeoa one-vessel operation by not removing the inert liquid tropic distillation. medium and the acid catalyst from the unsaturated ester When using an inert liquid medium, the reaction should intermediate, and by adding extra base in an amount be run at a temperature of 60-100 C., and the pressure 10 sufiicient to neutralize the acid catalyst and effect the should be adjusted so that the medium boils at the reac: ring closure. If the medium is water-immiscible, the salt tion temperature. The reaction is generally heated for of the uracil can be isolated as an aqueous solution by from 1 to hours or until little or no water evolves extracting with water. from the reaction. The reaction time will, of necessity, depend upon many variables, such as temperature, pres- 15 PROCEDURE AND 3 VARIABLES FOR sure, reactants, catalyst, and the rate at which the solvent is distilled. The addition of a sufficient amount of an aqueous solu- For maximum yield of product it is desirable to rapidly tion of an acid to lower the pH of the reaction mixture remove the Water which is formed and to avoid high ternto about 2-7 neutralizes the salts of the 3,6-substituted peratures. The resulting short reaction times at moderate 2 uracils and precipitates the acidic forms of these products temperatures minimize decomposition of reactants or of as a separate phase which can be easily separated from the unsaturated ester intermediate. the reaction mass by ordinary procedures. Any acid For initiation of the reaction and its successful operastronger than the uracil is satisfactory for this purpose. tion, it is necessary to have a catalyst present. This can Sulfuric and hydrochloric acids are preferred. be a hydrogen acid, a Lewis acid, an amine salt of a In aone-vessel operation, the reaction mixture obtained hydrogen acid or an ammonium sulfonate. Illustrative in step 2 containing the inert liquid, the salt of the deof these are sulfuric, hydrochloric, hydrobromic, hydrosired 3,6-subsrtiituted uracil, and the acid catalyst, is fiuoric, phosphoric, polyphosphoric, formic, maleic, pdiluted with sufficient Water andstirred to dissolve the toluenesulfonic, chloroacetic, and methanesulfonic acids; salt. The inert, water-immiscible liquid separates and FeCl BF or AlCl and methylammonium p-toluenecan be removed readily by conventional procedures. The sulfonate. Para-toluenesulfonic acid and sulfuric acid water layer is treated with acid to neutralize the 3,6- are the preferred catalysts. substituted uracil salt. The acidic form of the substituted The amount of catalyst employed varies with the speuracil then precipitates out of solution as a separate cific reactants used. Generally, however, 0.0005 to 1.0 phase. mole of catalyst per mole of ,B-keto or 'y-laetone ester is This invention will be better understood by referring sufficient. tothe following illustrative examples:

The reaction product is a mixture of the desired inter- Exam 1 mediate, 3-(3-substituted ureido)-2,3-unsaturated ester, I V p the acid catalyst, and residual starting materials, with or To a slurry of 290 Parts y Weight of ll-butylurea in without an inert liquid carrier. If unreacted urea is 40 1600 Parts Of benzene is added 325 Parts Of ethyl acetopresent as a solid at the end of the reaction, it can be acetate and 6 Parts Of P YP P acid- The mixture filtered from the reaction mixture. The catalyst need not is Stirred and refluxed for 43 hours, during which time Ihfi be removed since it is present in Such mall amounts Water fOI'i'I16d iS I'EII'IOVCd by aze'otropic distillation. The The reaction mixture is used directly in step 2, without resulting benzene Solution is decanted from a gummy furthe tre t t 45 fiesiciille and the binzene is removed from the solution by isti ation. To t e material remaining after this solvent PROCEDURE 33; $355 VARIABLES removal is added 135 parts of sodium methoxide in 1200 parts of ethanol. The mixture is heated to reflux for 15 If step 1 is run in the absence of a solvent, the unsatminutes. The ethanol is then removed by distillation, urated ester intermediate is diluted with an inert liquid the residue taken up -in 2000 parts of water, and the such as xylene, ethanol, toluene, methanol, ispropanol, aqueous mixture extracted twice with 500 parts of ethyl tetrahydrofuran, dioxane, benzene, or mixtures thereof. ether. The aqueous phase is then acidified with concen- If the catalyst is first neutralized, water can also be used trated aqueous hydrochloric acid, causing 3-butyl-6- a a diluent, methyluracil to precipitate from solution. The 3-butyl-6- In any event, the mixture is then heated for a short methyluracil is filtered, washed With water, and dried. time at about 55155 C. with 0100% excess of a strong The melting point of the product is 186l88 C. base such as sodium alkoxide, sodium hydroxide, or po- The uracils set out in Table I are prepared according tassium hydroxide. Sodium alkoxides contained in nonto the method of Example 1 by replacing the butylurea aqueous liquids are preferred as bases and media for this and ethyl acetoacetate with molecularly equivalent reaction step. Heating is continued for about 15 to 6O amounts of the ureas, thioureas, and ,B-keto esters also minutes. set forth in Table I.

TABLE I fl-Keto Ester Parts by Urea or Thionrea Parts by Substituted Uracil Product Weight Weight Ethyl acetoacetate 325 Butylthiourea 330 3-butyl-6-methyl-2-thlouracil.

Do 325 Isopropylthioure 295 3-isopropy1-6-methyl-2-th1ouraci1. Ethyl 3-ketovalerate. 360 Amylurea 325 B-amyl-ttethyluracil. Ethyl 3-ketohexanoate 395 Isoamylthrourem 365 3-isoamyl-6-propyl-2-thiouracil. Ethyl acetoacetate 325 Isobutylurea 290 3-isobutyl-fi-methyluracil. D0 325 Allylurea 250 3-allyl-6-methylnracil. Ethyl 3-ketoheptan0ate 430 Allylthiourea 290 3-allyl-fi-butyl-2-thi0uracll. Ethyl acetoacetate 325 Propynylurea 245 3-propynyl-6-methyluracil. Do 325 Hexylurea 360 3-hexyl-6-methyluraei1. Do 325 Phenylurea 339 B-phenyl-fi-methyluracll. Do 325 Isopr0pylurea 256 3-isopropyl-fi-methyluracil.

Example 2 A mixture containing 102 parts by weight of isopropylurea and 800 parts by weight of toluene is stirred tion containing 14' parts by weight of sodium methoxide and 40 parts by weight of methanol. The solution is refluxed for 10 minutes and then 200 parts by weight of water are added. On shaking, the sodium salt of the 2 522 3 18 i l zf 2 2 i y i i 5 desired uracil product dissolves in the water. The g if i g aqueous solution is separated from the organic layer b th Ce l d 1 and acidified. White, solid 3-cyclohexyl-6-methyluracil e mac Ion 15 con mucus y r f en eve is separated by filtration and dried. Its melting point is hem of water ceases, the toluene is stripped off and the 233 C residue is dissolved in 500 parts by Weight of absolute The uracil set out in Table n are prepared according ethyl alcohol. To this solution is added 44 parts by to h method f Example 3 by replacing h cycle. Welght 0f Sodlllm hydroxfikmlxtllrel 1S heated at hexylurea and ethyl acetoacetate with equivalent amounts reflux and stlrred until complete solution obtamed. of th ea thiour a a d a-ket esters l t f th The alcohol is distilled off and the residue is taken up in Table III.

TABLE III B-Keto Ester Parts by Urea or Thiourea Parts by Substituted Uracil Product Weight Weight Methyl 2-methyl 3 25. 4 Cyclooctylurea 33. 9 3-cyc1oocty1-5,6-dimethyluraeil.

0 28. 8 Cyclopentylthloure 29. 1 B-cyclopentyl-5-ethyl-ti-methyl-2-thiouraeil. Ethyl acetoaceta 25.4 Cycloheptylthiourea- 33.9 3-cycloheptyl-6-methyl-2thiouracil. Methyl 2-methyl-3-ketobutyrate. 25. 4 Cyclopentenylurea.-- 25. 9 3-eyc1opentenyl-5,6-dimethyluraeil. Ethyl 2-butoxy-3-ketobutyrate 40. 2 Decylurea 38.0 3-decyl-fi-butoxy-fi-methyluracil. Ethyl 2-ehloro-3-ketobutyrate. 32. 9 3-methoxypropylurea 26. 4 3- (3-methoxypropy1)-5-ehloro-6-methyluraeil. Ethyl 2-fiuoro-3-ketobutyrate 29.6 Norbornylmethylurea 33. 6 3-'(norbornylrnethyl)-5-fiuoro-6-methyluraeil. Ethyl Z-methoxy-S-ketobutyrate- 32.0 See.-butylurea 23. 2 3-sec.-butyl-5-n1ethoxy-6-n1ethyluraeil. Ethyl 2-brorno-3-ket0butyrate 41. 8 n-Pentylurea 26. 0 3-penytl-5-bromo-6-methyluraeil. Ethyl 2-eyano-3-ketobutyrate 31.0 4 chlorobenzylurea 36.8 '3-(4-ch1orobenzyl)-5-cyano-6-methyluracil. Ethyl 2rethoxy-3-ketobutyrate 35. 6 3-methylcyclohexylmethylurea 34.0 3-(3-ngfitlfylcyelohexylmethyl)-5-ethoxy-6- me yuraci Ethyl 2-methylthio-3-ketobutyrato 35. 2 Isopropylurea 20. 4 3-isopropyl-5-methylthio-0-methyluracil. Ethyl aoetoacetate 25. 4 Tert.-butylurea 23.2 3-tert.buty1-6-methyluraci1.

Do 25. 4 (l,3-dimethylbutyl)urea.. 28. 8 3-(1,3-dimethylbutyl)-6-methyluracil.

25. 4 Norbornylmethylurea 33. 6 3-(norbornylmethyl)-6-methyluracil.

D 25. 4 +meth0xyeyclohexylurea- 34. 4 3-(4-methoxyeyclohexyl)-6-methyluracil. Ethyl 2-bromo-3-ketobutyrate 41. 8 (l-ethylpropyDurea 26. 0 3-(l-ethylpropyl)-5-bromo-6-me thyluracil. Ethyl acetoacetate 3 25.4 Cyclohexylmethylurea- 31.2 3-cyc10hexylmethyl-G-methyluracil.

Ethyl 2-methyl-3-ketobutyrate 28. 2 Cyclohexylurea 28. 4 3-eyelohexyl-5,fi-dimethyluracil. Ethyl acetoacetate 25. 4 Norbornylurea 30. 8 3-norboruyl-G-methyluracil.

D0 25. 4 3a,4,5,6,7,7a-hexahydro-4,7- 38. 4 3-(3a,4,5,6,7,7a-hexahydro-4,7-methanoindenmethanoinden-5-ylurea. 5-yl)-6-methyluracil. Ethyl 2allyl-3-ketobutyrate 34. 0 (2-methy1cyelohexylmethyl)urea. 34. 0 3-(2-111ethylcyclohexylmethyl)-5-al1yl-6- v methyluracil.

in water. Neutral impurities are removed by washing Example 4 the Solutlon g gi ga g i i A mixture containing 404 parts by weight of isopropylcooled and am 1 e e 'lsopropy y uracl urea, 686 parts by weight of 'ethyI-Z-cyclopentanone-1- which precipitates as a white solid is filtered and dried.

The uracils set out in Table II are prepared according to the method of Example 2 by replacing the isopropylurea and ethyl acetoacetate with equivalent amounts of the ureas, thioureas, and fi-keto esters also set forth in carboxylate, 40 parts by weight of phosphoric acid, 1000 parts by weight of dioxane, and 879 parts by weight of benzene is stirred at reflux for 4 hours. During this time, the water given off bythe'reaction is trapped out of the distillate by azeotropic distillation. The solvent is re- Table II. moved by distillation and the solid residue is dissolved TABLE II B-Keto Ester Parts by Urea or Thiourea Parts by Substituted Uracil Product Welght Weight Ethyl 2 1nethyl-3-ketobutyrate 144 Methylurea 74 3,5,6-trimethyluracil.

D0 144 Phenylurea 136 3-phenyl-5,6-din1ethyluracil. Ethyl 2-butyl-3-ketovalerate. 199 p-Chlorophenylthlourea 186 3-(p-ehlorophenyl)-5-butyl-6-ethyl-2-thiouracil. Ethyl 2-ethyl-3-ketovalerate--. 171 m-Tqlyl r 3-(r11-t0lyl)-5,6-diethyluracil. Ethyl 2-methyl-3-ketooctanoate 199 p-Anlsylureaun 166 3-(p-anisyl)-5-n1ethyl-6-amyluraeil.

o 157 o-Nitrophenylthlourea 197 3-( rgnitropl ienyl)-5-eth 1-emeth l'2 iouraei. Ethyl 2-propyl-3 ketohexanoate 199 Allylur 100 3-511yl-5,6 dipropyluracil. Ethyl z-methyl-is-lxetobutyrate 144 fl-Ph n thylthi urea 3-(B-phenethyl)-5,6dimethyl-2rthiouraei1.

Example 3 in 2360 parts byweight of absolute ethanol containing A mixture containing 28.4 parts by weight of cyclohexylurea, 28.6 parts by weight of ethyl acetoacetate, 2.0 parts by weight of phosphoric acid, 100 parts by weight of dioxane, and 88 parts by weight of benzene is stirred and heated at reflux temperature. The water given off by the reaction is continuously distilled and trapped out of the distillate as the lower layer.

The resulting solution is ring closed in situ by adding a solu- 75 the isopropylurea and ethyl-Z-cyclopentanone-l-carbox-,

ylate with equivalent amounts of the ureas, thioureas, and keto esters also set forth in Table IV.

The benzene solution containing the intermediate is now stirred and refluxed for /2 hour with 37 parts by TABLE IV Keto Ester Parts by Urea or Thiourea. Parts by Alkoxide Uracil Salt Product Weight Weight Ethyl 2-cyclopentanone-1-earboxylate 162 Methylurea 74.0 Sodium methoxide 3-mtzlthyl-5,tfi-grimethyleneuracil,

so ium sa D 162 See.butylurea. 116.0 do 3-sIeIc.bu'tyl-5,6-trimethyleneuraeil,

a sa Ethyl 2-cyclohexanone-1-carb0xylate 187 Metliylurea 74.0 d0 3-rlrethsils-5,fi-tetramethyleneuracil,

asa D0 187 Cyclohexylurea 142.0 Potassium ethoxide... 3-cKyelollzexyl-5,fi-tetramethyleneuraeil,

sa Ethyl Z-cyclopentanone-l-earboxylate.- 162 do 142.0 Sodium ethoxide 3-% clohltzxyl-5,6-trimethyleneuracil,

asa Do 162 Allylthiourea 1000 do 3-%yl-5ig-trimethylene-2-thiouracil,

asa

Uracils can be obtained from uracil salts such as those listed in Table IV by dissolving the salt in parts by Weight of water and adding enough hydrochloric or sulfuric acid to .reduce the pH to 4.0. A solid essentially pure uracil will be for-med which is easily isolated by filtration.

Example 5 A mixture of 63.8 grams of isopropylurea, 65 grams of ethylacetoacetate, 0.94 gram of ammonium p-toluene sulfonate, and 440 grams of benzene is heated at reflux temperature for 7 hours, during which time 9 milliliters of water collects in the reflux line trap.

The mixture is cooled to room temperature, and the unreacted urea is filtered off.

29.5 grams of sodium methoxide are then added to the filtrate. The resulting mixture is heated at reflux temperature for minutes and then cooled to 65 C.

500 grams of water are then added, and the mixture is cooled to 30 C., whereupon the aqueous and organic phases separate.

The aqueous phase is removed and its pH adjusted to 6.2 by the addition of 13.7 milliliters of concentrated sulfuric acid. The resulting slurry is filtered, the solids are washed with 250 grams of water, and dried to give 64.5 grams of 3-isopropyl-6-methyluracil.

Example 6 The following compounds can be substituted for the ammonium ptoluene sulfonate in Example 5, with equivalent results:

weight of sodium methoxide. The mixture is then cooled and mixed well with 400 parts by weight of water. The basic aqueous layer is separated and neutralized with hydrocholric acid. The resulting white precipitate is filtered ofl, washed with 200 parts by weight of water at 10 C., and dried to give 3-isopropyl-6-methyluracil.

Example 8 A mixture of 426 parts by weight of cyclohexylurea,

423 parts by weight of 2-acetylbutyrolact0ne, 879 parts.

hexylureido crotonic acid, y-lactone.

A mixture 01f 302 parts by weight of the 2-(2-hydroxyethyl) 3 (3-cyclohexylureido)crotonic acid, 'y-lactone, 1580-parts by weight of absolute ethanol, and 130 parts by weight of sodium methoxide is refluxed for -15 minutes. It is then concentrated to dryness at reduced pressure, and the residue is dissolved in 1500 parts by weight of water.

This solution is cooled, acidified with hydrochloric acid to pH 5, and the resulting white precipitate, 3-cyclohexyl-S-(Z-hydroxyethyl)-6-methyluracil, is filtered ofl, dried, and recrystallized from a mixture of ethanol and water.

Grams The uracils set out in Table V are prepared according Concentrated sulflll'lc 361d t0 the method of Example 8 by replacing the cyclohexyl- Isopropylammomum sulfate 1.1 urea and Z-acetylbutyrolactOne with equivalent amounts Triethylammonium p-toluene sulfonate 1.40 of the ureas, thioureas, and 'y-lactones also set forth in Methylammonium p-toluene sulfonate 1.0 Table V.

TABLE V B-Keto Lactone Parts by Urea 0r Thiourea Parts by Substituted Uracil Product Weight Weight Z-acetylbutyrolactone 423 Isopropylurea 306 5-(2-hydroxyethyl)-fi-methyl-3-isopropyluracil. Do 423 Isopropylthiourea 354 5-(%hydroiiyethyl)-6-rnethyl-3-isopropyl-2- t iouraci.

423 Sec.-butylurea 348 3-sec.-butyl-5-(2-hydroxyethyl) -6-methyluracil.

423 Pheuylurea 407 a(2-hydroxyethyl)-6-methyl-3-phenyluracil.

423 p-Chlorophenylurea 515 3-(4-ehlorophenyl)-5-(2-hydroxyethyl)-6- methyluraoil. 2-aeetyl-(3,4-diethyl)-butyrolactone 468 3,4-dichlorophenylurea 615 3-(3,4-dich1orophenyl)-5-(1-ethyl-2hydroxybutyD-dmethyluracil.

Example 7 Example 9 A mixture of 440 parts by weight of benzene, 63.7 parts by weight of isopropylurea, parts by weight of ethyl acetoacetate, and 0.94 part by weight of ferric chloride is stirred and refluxed.

The water given off is azeotropically distilled out of the reaction medium and collected in a trap by upward displacement of benzene. When water evolution ceases, the mixture is cooled. Excess isopropylurea crystallizes and is filtered oil.

A mixture of 657 parts by weight of isopropylurea, 725 parts by weight of methyl acetoacetate, 1350 parts by weight of xylene and 3 parts by weight of concentrated sulfuric acid is stirred and refluxed for 14 hours at C. and a pressure of 110 mm. of Hg. During this time, parts by weight of water is removed from the reaction mass.

To this reaction mass, at atmospheric pressure and 80 C., are added 1550 parts by weight of a 24% solution Three recrystallizations of the resulting solid from acetonitrile give 2-(2-hydroxyethyl)-3-cyclo- 1 1 of sodium methoxide in methanol; Fifteen hundred to 1700 parts by weight of the methanol-xylene solution are then distilled off.

Forty-eight hundred parts by weight of water are then added to the reaction mass and the mixture is agitated thoroughly. The phases are then allowed to separate at 70 C. The aqueous phase is drawn ofl and brought to pH 5.9 with concentrated sulfuric acid.

The resulting slurry is cooled to room temperature and the solid 3-isopropyl-6-methyluracil is filtered, washed with water, and dried.

Example A mixture of 786 parts by weight of methylacetoacetate, 986 parts by weight of isopropylurea, 658 parts by weight of xylene and 3 parts by weight of sulfuric acid is stirred and refluxed for 14 hours at 87 C. and a pressure of 100 mm. of murcury. During this time, 115 parts by weight of water are removed from the reaction mass.

The vacuum is then released and 560 parts by weight of sodium methoxide are slowly added to the reaction mass at 86 C. The mixture is held at 80-90" C. for 30 minutes and is then extracted with 9000 parts by weight of water. The aqueous phase is brought to a pH of 6.5 with concentrated sulfuric acid; the resulting slurry of 3-isopropyl-6-methyluracil is filtered, washed with water, and dried.

Example 11 A mixtureof 797 parts by weight molar excess) of isopropylurea, 812 parts by weight of ethylacetoacetate, 1350 parts by weight of xylene, and 5 parts by weight of p-toluenesulfonic acid is stirred and refluxed for 14 hours at 85 C. and a pressure of 110 mm. of mercury. During this time, 93 parts by weight of water are removed from the reaction mass.

The reaction mass is then cooled to room temperature and excess isopropylurea is removed by filtration. The urea filter cake is washed with 260 parts by Weight of xylene; this xylene is then'added to the filtrate.

To this solution are added 371 parts by weight of powdered sodium methoxide. The resulting slurry is heated to 80 C. and stirred for minutes. It is then cooled to 25 C. and 6500 parts by weight of water are added. This mixture is stirred for 5-10 minutes and the phases are then allowed to separate.

The aqueous phase is removed and brought to a pH of 6.1 with concentrated sulfuric acid. The resulting slurry of 3-isopropyl-6-methyluracil is filtered, washed with water, and dried.

Example 12 A mixture of 725 parts by Weight of methylacetoacetate, 657 parts by weight (3% molar excess) of isopropylurea, 1350 parts by weight of xylene, and 5 parts by weight of sulfuric acid is stirred and refluxed for 14 hours at 82 C. and a pressure of 110 mm. of mercury.

During this time, 93 parts by weight of water are removed from the reaction mass.

With the temperature at 80 C., 370 parts by weight of sodium methoxide are then slowly added to the mixture and the temperature is held at 80 C. for 30 minutes. The mixture is then cooled to 60 C. and extracted with 6500 parts by weight of water. The aqueous layer is separated and brought to a pH of 6.0 with concentrated sulfuric acid. The resulting slurry of 3-isopropyl-6-methyluracil is filtered, washed with water, and dried.

The methylacetoacetate in this example can be replaced with 812 parts by weight of ethylacetoacetate, with similar results.

Example 13 I A mixture of363 parts by weight of sec.-butylurea, 325 parts by weight of ethyl acetoacetate, 2500 parts by weight of xylene, and 5 parts by weight of p-toluenesulfonic acid is stirred and refluxed for 14 hours at 82 C. and a pressure of 110 mm. of mercury. During this time, 42 parts by weight of water are removed from the mixture. 1

To this mixture, at room temperature, are added 148 parts 'by weight of sodium methoxide. This mixture is then heated to C. and held there for 30 minutes. The mixture is then cooled to 60 C. and extracted with 800 parts by weight of cold tap water. The aqueous phase is brought to a pH of 6.0, and the resulting slurry of 3-sec.-butyl-6methyluracil is filtered, washed with water, and dried.

Example 14 A mixture of 130 g. sec.-butylurea, 125 g. methylacetoacetate, 225 g. xylene, and 0.75 g. sulfuric acid is heated to reflux at a pressure of mm. (absolute), with agitation. Enough heat is supplied to reflux the mixture at 40 to 45 g./min.' This reflux is passed to a decanter, where water is separated before returning the xylene phase to the reactor.

After four hours, during which time the temperature of the reaction mixture rises from 80 to 87 C., the rate of water removal drops to less than 0.5 g./hr., and 16.1 g. of water (calculated after analysis of the aqueous layer from the decanter) have been collected.

Reflux is terminated and a solution of 64 g. of sodium methoxide in 150 g. of methanol is rapidly added to the reactor. The mixture is then heated to 90 C., with distillation, over a period of 30 to 60 minutes. Water, 650 g. is rapidly added and the two-phase system is stirred to extract the sodium salt of 3-sec.-butyl-6- methyluracil into the aqueous phase.

This mixture is then cooled to 50 C. and the phases separated. The lower aqueous phase contains 186 g. of the sodium salt of 3-sec.-butyl-6-methyluracil and can be used directly as a herbicide, or if desired, the free uracil can be isolated from it by cooling it to 10 C. and adding sufficient 2.5 N aqueous hydrochloric acid to reduce the pH to 6.0, while maintaining the temperature below 15 C. with external cooling. The resulting slurry is. then filtered, the solids washed with two ice cold 200 mL-portions of water and dried at 60 C. in a' vacuum oven. There are obtained 133 g. of 3-sec.-butyl- 6-methyluracil.

Example 15 A mixture of 660 g. of sec.-butylurea, 600 g. of methylacetoacetate, 1080 g. of xylene and 3.6 g. of sulfuric acid are heated to reflux at 70 mm. pressure (absolute) to give a reflux rate of -125 mL/min. The reflux is passed to a decanter where water is separated from the reflux before returning the xylene phase to the reactor.

After five hours there are collected from the decanter 90 g. of a water phase analyzing 93% H O. At this point the rate of water removal has decreased to about 0.8 g./hr. and the reaction is terminated.

Sodium methoxide solution (1370 g., 29.3% sodium methoxide in methanol) is added rapidly and the reaction mass is heated to 90 C. over a one-hour period to distill 1180 g. of a methanol-xylene mixture. Water, 2500 g., is added to the residue which is then agitated for 15 minutes.

On separating the phases there are obtained 930 g. of a xylene phase which can be recovered for recycle, and 4100 g. of an aqueous phase analyzing 20.3% 3-sec.- butyl-6-methyluracil. This uracil is in solution as its sodium salt and, as such can be used as a herbicide. Alternatively, the purified uracil can be isolated as described in Example 14.

l3 The claims are:

1. The process for preparing a uracil compound having the formula where:

R is selected from the group consisting of alkyl of 1 through 10 carbon atoms,

substituted alkyl of 1 through 8 carbon atoms, wherein said substituent is selected from the group consisting of bromine, chlorine, hydroxy, alkoxy, alkoxycarbonyl, and cyano,

aryl of 5 through carbon atoms,

substituted phenyl, wherein said substituent is selected from the group consisting of chlorine, bromine, fluorine, alkoxy, alkyl of 1 through 6 carbon atoms, nitro, trifluoromethyl, 1,2-tetramethylene, and 1,2-trimethylenylene,

aralkyl of 5 through 13 carbon atoms,

substituted aralkyl of 5 through 13 carbon atoms, wherein said substituent is selected from the group consisting of chlorine, nitro, alkyl, and alkoxy,

tetrahydronaphthylalkyl,

alkenyl of 3 through 8 carbon atoms,

alkynyl of 3 through 8 carbon atoms,

cycloalkyl of 3 through 12 carbon atoms,

substituted cycloalkyl of 3 through 12 carbon atoms, wherein said substituent is selected from the group consisting of bromine, chlorine, methoxy, and alkyl,

cycloalkenyl of 4 through 12 carbon atoms,

substituted cycloalkenyl of 4 through 12 carbon atoms, wherein said substituent is selected from the group consisting of bromine, chlorine, methoxy, and alkyl,

cycloalkyl alkyl of 4 through 13 carbon atoms,

cycloalkenyl alkyl of 5 through 13 carbon atoms,

(substituted cycloalkyDalkyl of 5 through 14 carbon atoms, wherein said substituent is selected from the group consisting of bromine, chlorine, methoxy, and alkyl, and

(substituted cycloalkenyDalkyl of 5 through 14 car bon atoms, wherein said substituent is selected from the group consisting of bromine, chlorine, methoxy, and alkyl;

R is selected from the group consisting of hydrogen, chlorine, fluorine, bromine, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, alkenyl of 3 thruogh 6 carbon atoms, cyano, alkylthio of 1 through 4 carbon atoms, and hydroxy alkyl of 2 through 6 carbon atoms;

R is alkyl of 1 through 5 carbon atoms;

X is selected from the group consisting of oxygen and sulfur; and

M is selected from the group consisting of hydrogen,

sodium, potassium and lithium;

with the proviso that R and R can be linked together by a methylene bridge of the formula (CH where n is a number 3 through 5; said process comprising (a) heating a urea of the formula Where R and X have the same meaning as above with a B-keto ester of the formula where R and R have the same meaning as above, and R is an alkyl radical containing from 1 to 6 carbon atoms, the ester-urea mole ratio ranging from 0.7-1.30 to 1, at a temperature of from 60 to C. in the presence of from 0.000 5 to 1.0 mole of an acid catalyst per mole of said ,B-keto ester and an inert, water-immiscible liquid medium, while effecting the continuous removal of the water of reaction from the reaction mixture by azeotropic distillation so as to form a substituted ureido ester of the formula where R R R R and X have the same meaning as above;

(b) heating said substituted ureido ester at a temperature of from 55 to C. for from 15 to 60 minutes with a strong base, in an inert liquid medium, to form a uracil salt;

(c) converting said uracil salt to its acidic form by contacting with an acid stronger than the uracil portion of said salt; and

(d) recovering said acidic form from the reaction mass of step (c) as the uracil product.

2. The process for preparing a uracil compound having the formula ll 1 l a CHCHOH where:

R is selected from the group consisting of alkyl of 1 through 10 carbon atoms, substituted alkyl of 1 through 8 carbon atoms, wherein said substituent is selected from the group consisting of bromine, chlorine, hydroxy, alkoxy, alkoxycarbonyl, and cyano,

aryl of 5 through 10 carbon atoms,

substituted phenyl, wherein said substituent is selected from the group consisting of chlorine, bromine, fluorine, alkoxy, alkyl of 1 through 6 carbon atoms, nitro, trifluoromethyl, 1,2-tetramethylene, and 1,2-trirnethylenylene,

aralkyl of 5 through 13 carbon atoms,

substituted aralkyl of 5 through 13 carbon atoms, wherein said substituent is selected from the .group consisting of chlorine, nitro, alkyl, and alkoxy,

tetrahydronaphthylalkyl,

alkenyl of 3 through 8 carbon atoms,

alkynyl of 3 through 8 carbon atoms,

cycloalkyl of 3 through 12 carbon atoms,

substituted cycloalkyl of 3 through 12 carbon atoms, wherein said substituent is selected from the group consisting of bromine, chlorine, methoxy, and alkyl,

cycloalkenyl of 4 through 12 carbon atoms,

substituted cycloalkenyl of 4 through 12 carbon atoms wherein said substituent is selected from the group consisting of bromine, chlorine, methoxy, and alkyl,

cycloalkyl alkyl of 4 through 13 carbon atoms,

cycloalkenyl alkyl of 5 through 13 carbon atoms,

(substituted cycloalkyl)alkyl of 5 through 14 carbon atoms, wherein said substituent is selected from the group consisting of bromine, chlorine, I

from the group consisting of bromine, chlorine, methoxy, and alkyl; R is alkyl of 1 through 5 carbon atoms;

R and R are selected from the group consisting of hydrogen and alkyl of 1 through 4 carbon atoms; X is selected from the group consisting of oxygen and sulfur; and M is selected from the group consisting of hydrogen,

sodium, potassium and lithium; said process comprising (a) heating a urea of the formula X R1NH( iNHz where R; and X have the same meaning as above with about an equivalent weight of a -lactone of the formula OT -C-R3 E R5 where R R and R have the same meaning as above,

at a temperature of from 60 to 100 C. in the presence of 0.0005 to 1 mole of an acid catalyst per mole of said 'y-lactone and an inert, wateri-mmiscible liquid medium, while elfecting the continuous removal of the water of reaction from the reaction mixture by azeotropic distillation so as to form an intermediate of the formula R O H 3 Re 11 Re where R R R R and X have the same meaning as above;

(b) heating said intermediate at a temperature of from 55 to 155 C. for from to 30 minutes with a base selected from the group consisting of alkali metal hydroxides and alkoxides containing from 1 to 4 carbon atoms in an inert liquid medium, to form a uracil salt;

(c) converting said uracil salt to its acidic form by contacting with an acid stronger than the uracil portion of said salt; and

(d) recovering said acidic form from the reaction mass of step (c) as the uracil product.

3. A process according to claim 1 wherein 3-sec.- butyl-6-methyluracil is formed by reacting sec.-butylurea with a compound selected from the group consisting of methyl acetoacetate and ethyl acetoacetate.

4. A process acc-ording to claim 1 wherein 3-cyclohexyl-S,6-trimethyleneuracil is formed by reacting cyclohexylurea with 2-carbethoxycyclopentanone.

5. A process according to claim 1 wherein 3-(2-norbonrylmethyl)-6-rnethyluracil is formed by reacting 1- (2-norbornylmethyl)urea with a compound selected from the group consisting of methyl acetoacetate and ethyl acetoacetate.

6. A process according to claim 1 wherein 3-isobutyl- 6-methyluracil is formed by reacting isobutylurea with a compound selected from the group consisting of methyl acetoacetate and ethyl acetoacetate.

7. A process according to claim 1 wherein 3-( l-ethylpropyl)-6methyluracil is formed by reacting 1-(3-amyl) urea with a compound selected from the group consisting of methyl acetoacetate and ethyl acetoacetate.

8. A process according to claim 1 wherein 3-tert.-buty1- 6-methyluracil is formed by reacting tert.-butylurea with a compound selected from the group consisting of methyl acetoacetate and ethyl acetoacetate,

9. A process according to claim 1 wherein 3-(1,3- dimethylbutyl)-6-methyluracil is formed by reacting l- (1,4- dimethylbutyl)urea with a compound selected from the group consisting of methyl acetoacetate and ethyl acetoacetate.

References Cited by the Examiner UNITED STATES PATENTS 2,444,024 6/ 1948 Archer 260260 2,820,035 1/1958 Schefiler et al. 260-260 X 2,899,435 8/ 1959 Brandstrom 2 60-260 X 2,937,175 5/1960 Scriabine 260260 Donleavy et al.: Organic Syntheses, Collective Volume II, pages 422-423, 1943.

Senda et al.: Chemical and Pharmaceutical Bulletin (Japan), volume 6, pages 476-479, 1958. [Note: Abstracted in Chemical Abstracts, volume 53, page 10327d, 1959.]

NICHOLAS S. RIZZO, Primary Examiner.

JAMES W. ADAMS, Assistant Examiner. 

1. THE PROCESS FOR PREPARING A URACIL COMPOUND HAVING THE FORMULA 